Severe ischemic events including cerebral infarction, cardiac infarction, or pulmonary embolism occur as a result of local occlusion of the blood flow; i.e., ischemia. In cerebral infarction, the ischemic core at an acute stage leads irreversibly to death even though the blood flow is restored, while there is a reversible, incomplete ischemic region around the ischemic core, which is called “penumbra.” The ischemic core expands unless it is treated, and the penumbra gradually disappears. As a result, the region with cerebral infarction expands pathologically, and functional disorders are caused clinically, leading to death at worst. The purpose of treatment at an acute stage of cerebral infarction is to restore the blood flow. This restoration depends on the extent and the continuation time of ischemia. That is, early recovery of cerebral infarction depends on whether the blood flow in the penumbra can be restored rapidly.
Tissue plasminogen activator (hereinafter “t-PA”) is approved as a therapeutic drug for ischemic events at an acute stage, since it is effectively used for a thrombolytic therapy where an ischemia-causing thrombus is lysed to resume blood supply.
Administration of t-PA, however, is ineffective if administered after an acute stage of ischemic events. In cerebral infarction, the t-PA rather causes concomitantly occurring cerebral hemorrhage and exacerbation of prognosis. Thus, the administration of t-PA is contraindicated after an acute stage of cerebral infarction; i.e., after 3 hours or longer has passed since the onset of the cerebral infarction. In cardiac infarction, the administration of t-PA is contraindicated for patients after 6 hours or longer has passed after the onset of cardiac infarction.
Thrombolytic therapy for treating ischemic events involves a particularly high risk of cerebral hemorrhage. Any thrombolytic therapy for reducing severity of ischemic conditions has factors increasing risk, such as risk of cerebral hemorrhage (see Fitchett, D., Can. J. Cardiol. (2007) 23:663-671). This includes mechanical thrombolysis as well as biochemical thrombolysis.
Therefore, keen demand has arisen for development of a treatment that can be administered to a patient after an acute stage of severe ischemic events including cerebral infarction, cardiac infarction, or pulmonary embolism without inducing complications such as cerebral hemorrhage.